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Treatment regimens in ovulation induction and ovarian hyperstimulation

van Wely, M.

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Citation for published version (APA):van Wely, M. (2004). Treatment regimens in ovulation induction and ovarian hyperstimulation.

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Download date: 10 Sep 2020

Chapterr 1

Introduction n

9 9

Chapterr 1

Inn reproductive medicine, manipulating ovarian function remains one of the more

challengingg topics. Two types of intervention can be distinguished, namely ovulation

inductionn and ovarian hyperstimulation. In ovulation induction one aims for the development

off one mature follicle, while in ovarian hyperstimulation one intends to stimulate the

developmentt of multiple mature follicles.

Ovulationn induction

Ovulationn induction is indicated in women with ovulation disorders. In about 90% of these

womenn polycystic ovary syndrome (PCOS) can be diagnosed. PCOS is a leading cause of

femalee infertility and is observed in approximately 4-7% of all women.1"3 The disorder is

characterisedd by oligo- or amenorrhea and the formation of multiple follicular cysts of 10

mmm or smaller in the ovaries, a process related to the ovarian failure to develop a mature

follicle.. Symptoms may include infertility, hirsutism, acne, obesity and a pre-diabetic state

withh insulin resistance or hyperinsulinaemia. Furthermore, PCOS can have significant long-

termm effects, including diabetes and cardiovascular disease4"10 and presumably endometrial

orr breast cancer.2" -12

Inn North America diagnosis of PCOS used to be predominantly based on the presence of

hyperandrogenism,, while in Europe PCOS was generally diagnosed on the basis of the

presencee of polycystic ovaries.4'6'13'14 Recently, consensus was reached on an international

standardd for the diagnosis of PCOS. The revised diagnostic criteria include at least two out

off the following three criteria: oligo- or anovulation, clinical or biochemical signs of

hyperandrogenismm and presence of polycystic ovaries. A polycystic ovary is defined as 12 or

moree follicles in each ovary measuring 2-9 mm in diameter, and/or an increased ovarian

volume,, i.e. a volume of at least 10 ml.' '6

Strategiess to induce ovulation include oral anti-oestrogens, parenteral gonadotrophin therapy,

laparoscopicc ovarian surgery and insulin sensitisers. The oral anti-oestrogen clomiphene

citratee (CC) is at this moment the treatment of choice. It binds to oestrogen receptors in

hypothalamuss and pituitary gland. This results in secretion of gonadotrophin-releasing

hormonee (GnRH) with a consequent release of the gonadotrophins LH and FSH that trigger

folliculogenesis.. About twenty percent of the women with PCOS will not ovulate on

CC.71117"199 The second line treatment in these clomiphene citrate resistant women may be

ovulationn induction with gonadotrophins or laparoscopic ovarian surgery. The basic idea

behindd ovulation induction with gonadotrophins is to stimulate the follicles directly and

moree vigorously than is done with CC therapy.

Humann gonadotrophin preparations may contain FSH only or a combination of FSH and LH.

Gonadotrophinn preparations are derived from urine of post-menopausal women or can be

10 0

Introduction n

producedd as recombinant FSH by transfected stable Chinese hamster ovary cell lines.

Treatmentt leads to ovulation in about 70 - 80% of the cycles started and results in an average

cumulativee pregnancy rate of about 38% per woman.20-21

Thee major disadvantages of ovulation induction with gonadotrophins are the high

cancellationn rate due to multifollicular development and the risk of higher order multiple

pregnancies.. These treatment risks are even more significant in women with PCOS due to

thee high sensitivity of polycystic ovaries to exogenous gonadotrophins. Multiple pregnancy

ratess varying from 6 up to 35% have been reported depending on the protocol used.21"23

Probably,, the safest approach for ovulation induction with gonadotrophins in PCOS is the

chronicc low dose step-up regimen that employs a maximal starting dose of 75 IU of FSH.21

Iff there is no response after 14 days, the starting dose is increased by 37.5 IU every seven

days.. Related to the notion of a "threshold" FSH concentration, the goal is to not exceed the

FSHH concentration above which more than one follicle will respond.23'24 This approach may

requiree as much as 20 to 25 days of stimulation, but carries the lowest risk for multifollicular

developmentt and an almost zero risk of the ovarian hyperstimulation syndrome.25 A further

disadvantagee of ovulation induction with gonadotrophins are the high costs associated with

thiss form of treatment.

Ovariann surgery is an alternative treatment option for ovulation induction in women with

CC-resistantt PCOS. Surgical ovarian wedge resection was the first established treatment

shownn to induce ovulation in women with PCOS.26 The procedure was abandoned because

off the risk of post-operative adhesion formation leading to mechanical infertility. In recent

yearss the rapidly expanding field of operative laparoscopy has led to a renewed interest for

surgicall treatment for PCOS. A number of laparoscopic approaches have been used,

includingg laser, unipolar electrocautery, and bipolar electrocautery. The advantages of

laparoscopicc laser surgery are a shorter operating time and diminished risk of adhesions

comparedd to electrocautery. However, the laser systems are expensive and require more

extensivee and costly upkeep, which is probably why electrocautery is most commonly being

used.. In ovarian electrocautery multiple perforations of the ovarian surface and stroma are

created.27"366 This procedure has been shown to lower levels of LH, testosterone, and other

hormoness that are characteristically elevated in these women.29'30'32,36 The working

mechanismm is as of yet unknown. One theory hypothesises that cautery reduces the enlarged

cohortt of available antral follicles in the ovaries of women with PCOS. A reduction in the

numberr of antral follicles would lead to a lower basal inhibinB concentration being produced

byy the granulosa cells and consequently to a relative increase in FSH, inducing follicular

growthh and spontaneous ovulations.9,10 A second theory suggests that cautery is effective

11 1

Chapterr 1

throughh the destruction of ovarian stromal cells, which produce androgens. The subsequent

reductionn of ovarian hyperandrogenism might restore ovulation.37

Laparoscopicc electrocautery of the ovaries leads to ovulation in about 70 - 80% of the cycles

startedd and results in approximately 40% of woman achieving a pregnancy.38 Uncontrolled

studiess have demonstrated that some anovulatory women respond to clomiphene citrate after

electrocauteryy of the ovaries.27"29'33'34'36 The disadvantages of a laparoscopic procedure are

thatt it is a surgical procedure, that general anaesthesia is needed, and that possible long term

effectss on ovarian function are unknown.

Bothh ovulation induction with recombinant FSH (rFSH) and laparoscopic electrocautery of

thee ovaries are standard treatments in women with CC-resistant PCOS. Whether

gonadotrophh ins or laparoscopic electrocautery of the ovaries should be the treatment of

choicee in women with CC-resistant polycystic ovary syndrome was unclear when work on

thiss thesis was started. To find out the best way to treat these women, we designed a

randomisedd clinical trial comparing a treatment strategy that started with laparoscopic

electrocauteryy of the ovaries followed by CC and rFSH if anovulation persisted versus

ovulationn induction with rFSH. We hypothesised that the electrocautery strategy would lead

too more women getting pregnant at lower costs.

Inn deciding which treatment to give to a woman it would be helpful if we could predict

ovariann response and treatment outcome beforehand. An informed decision to use

electrocauteryy or ovulation induction with rFSH would benefit from knowledge about the

chancess of success or failure with these respective procedures in specific subgroups of

women.. Such knowledge was not available at the time we planned our studies.

Ovariann hyperstimillation

Somee women with PCOS will not respond to ovulation induction, while in others ovulation

inductionn is not opportune as other fertility problems co-exist. In these women, ovarian

hyperstimulationn for in vitro fertilisation and embryo transfer (IVF-ET), and intra-

cytoplasmaticc sperm injection (ICSI) in case of an additional male factor infertility, is

consideredd a last resort treatment.39"41 It is standard practice to use gonadotrophins for

ovariann hyperstimulation to achieve multiple follicular development in women with

infertilityy undergoing treatment with assisted reproductive techniques (ART). Both human

menopausall gonadotrophins (hMG) and FSH preparations have been used successfully for

thiss purpose. The presumed redundancy of LH and the wish for a more purified product

drovee the conversion from hMG to urinary FSH (uFSH). Subsequently, highly purified and

12 2

Introduction n

recombinantt FSH (rFSH) entered the market and replaced earlier FSH products. Its purity,

batch-to-batchh consistency and availability make it an attractive alternative to the urinary

FSHH products.

Inn recent years, virtually all IVF cycles undertaken include a gonadotrophin-releasing

hormonee (GnRH) agonist. Prolonged use of GnRH agonists results in down-regulation of the

pituitaryy and is used in assisted reproduction cycles to prevent an LH surge that would

inducee premature ovulation. Studies have shown that the addition of GnRH agonists results

inn higher pregnancy rates, lower miscarriage rates and fewer cycle cancellations, compared

too the use of gonadotrophins alone, both in women with and without PCOS.41'42

Whetherr a pure FSH preparation or a mixture of LH and FSH should be preferred for ovarian

hyperstimulationn in GnRHa down-regulated women has been a matter of debate in the

literaturee over the last five years.43"48 Especially in women with PCOS, who often have

elevatedd LH levels, the use of pure FSH is theoretically appealing. Yet, when work on this

thesiss was started there was littl e evidence to support pure FSH preparations over LH-

containingg gonadotrophins.

Theree also is considerable difference between the available FSH preparations with regard to

theirr composition. FSH is a glycosylated peptide hormone composed of two peptide

subunits,, an a- and a (3-subunit. Each peptide subunit possesses two glycosylation sites on

whichh oligosaccharides are normally attached. Each oligosaccharide may show single

branched,, di- tri- and even tetrabranched structures and each branch of the oligosaccharides

mayy or may not terminate in a negatively charged sialic acid residue allowing FSH to exist

ass a number of isoforms.49 These isoforms differ in their isoelectric points, the lower the

isoelectricc point the more acidic will be the FSH isoform. There is evidence that the acidity

off the FSH isoforms affect its biological activity and circulatory half-life.50'52 Recombinant

andd urinary FSH preparations are known to differ in isoform composition.53 At the time we

plannedd our studies, the FSH isoform profiles of commercially available gonadotrophin

preparationss had not been a factor when evaluating treatment outcome in connection with

ART. .

13 3

Chapterr 1

Aimm of this thesis

Thee aim of this thesis is to answer the following questions:

1.. How does a laparoscopic electrocautery strategy compare with ovulation induction with

rFSHH in CC-resistant women with PCOS in terms of clinical outcome and costs?

2.. What are predictors of ovarian response after laparoscopic electrocautery of the ovaries

andd of treatment outcome after laparoscopic electrocautery of the ovaries followed by

clomiphenee citrate?

3.. Which patient characteristics can predict treatment outcome following ovulation

inductionn with rFSH

4.. What is the effectiveness of hMG, uFSH and rFSH for ovarian hyperstimulation in IVF

andd ICSI cycles in women with PCOS?

5.. How do hMG and rFSH compare in terms of clinical outcome when used for ovarian

hyperstimulationn in IVF and ICSI cycles in normogonadotrophic ovulating women ?

6.. Is the FSH isoform profile of gonadotrophin preparations of clinical significance?

14 4

Introduction n

Outlinee of this thesis

TheThe first part of this thesis (Chapters 2 to 5) addresses ovulation induction in women with

CC-resistantCC-resistant PCOS.

Chapterr 2 reports on the results of a randomised clinical trial that compared the

effectivenesss of a laparoscopic electrocautery strategy and ovulation induction with

recombinantt FSH in CC-resistant women with PCOS. This trial was performed in 29 Dutch

hospitalss between 1998 and 2001. Primary outcome was an ongoing pregnancy.

Chapterr 3 reports on the economic evaluation of a laparoscopic electrocautery strategy

comparedd to ovulation induction with recombinant FSH using data of the randomised

clinicall trial from Chapter 2. Data on used recourses were collected and costs of both

treatmentt modalities were calculated. A scenario analysis was done to estimate the costs of

ovulationn induction with rFSH without a preceding laparoscopy.

Chapterr 4 contains a study of clinical, ultrasonographic and endocrine characteristics

obtainedd during initial screening of CC-resistant PCOS patients that can predict persistence

off anovulation after laparoscopic electrocautery. Persistence of anovulation was defined as

failuree to ovulate within eight weeks after electrocautery. Subsequently it was studied

whetherr clinical, ultrasonographic and endocrine characteristics during initial screening of

cc-resistantt PCOS patients may predict treatment failure after electrocautery followed by CC

inn case of persistent anovulation. Treatment failure was defined as failure to reach an

ongoingg pregnancy.

Chapterr 5 documents the ability of clinical, ultrasonographic and endocrine characteristics

duringg initial screening of CC-resistant PCOS patients to predict treatment success following

ovulationn induction with rFSH. Treatment success was defined as reaching an ongoing

pregnancy. .

TheThe second part of this thesis (Chapters 6 to 8) deals with ovarian hyperstimulation.

Chapterr 6 presents the results of a retrospective study comparing pregnancy outcome

followingg treatment with hMG, uFSH and rFSH for IVF and ICSI in women with PCOS,

whilee adjusting for other explanatory variables.

15 5

Chapterr 1

Chapterr 7 provides a systematic review of the published literature in which hMG was

comparedd to rFSH for ovarian hyperstimulation in IVF and ICSI in normogonadotrophic

ovulatingg women. Primary outcome was ongoing pregnancy or live birth.

Chapterr 8 reviews what is known on biological differences of various FSH isoforms and

studiess in a meta-analysis the clinical effectiveness of Metrodin-HP and Gonal-F, two FSH

productss that differ most profoundly in isoform composition.

Chapterr 9 summarises the results of the preceding chapters, presents conclusions and gives

suggestionss for further research.

16 6

Introduction n

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